methyl 4-bromo-2-hydroxybenzoate

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 139 g of ground potassium carbonate, 470 ml of acetonitrile, 16 g of benzyltributylammonium chloride and 136 g of allyl bromide were introduced into a 3-liter round-bottomed flask and 236 g of ground methyl 4-bromosalicylate were added in small amounts. The contents were heated under reflux with vigorous stirring, for 5 hours and then a part of the acetonitrile was distilled off under slight vacuum and the residue was taken up with water. A precipitate of methyl 2-allyloxy-4-bromobenzoate was obtained, which was drained, washed with water and air-dried. The contents were heated under reflux with vigorous stirring, for 5 hours a part of the acetonitrile was distilled off under slight vacuum

Conditions: temp:60.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a 70 ml dimethylformamide solution of 5.0 g (21.7 mmol) of methyl 4-bromo-2-hydroxybenzoate, 3.4 ml (32.6 mmol) of methyl chlorodifluoroacetate and 3.0 g (21.7 mmol) of potassium carbonate were added. The mixture was stirred at 60° C. for 6 hours and at room temperature for 60 hours. Then, water was added to the reaction mixture, and the mixture was extracted with ether. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1) to obtain 1.4 g (23%) of the captioned compound. the mixture was extracted with ether The organic layer was washed with water The washed system was dried over anhydrous sodium sulfate the solvent was distilled off under reduced pressure The residue was purified by silica gel column chromatography (hexane/ethyl acetate=8/1)

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88%) as white crystals. The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected concentrated recrystallized from ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88%) as white crystals. The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected concentrated recrystallized from ethyl acetate-hexane

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-Bromosalicylic acid (15.5 g, 71 mmol) was dissolved in methanol (500 ml), and concentrated sulfuric acid (9.7 g, 99 mmol) was added thereto. The reaction mixture was refluxed for 24 hrs, and the solvent was evaporated. The residue was neutralized with 2 N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:20, v/v) were collected and concentrated to give methyl 4-bromosalicylate (8.7 g, 52%). Methyl 4-bromosalicylate (8.7 g, 37 mmol) and N,N-dimethylthiocarbamoyl chloride (6.0 g, 48 mmol) were dissolved in DMF (80 ml), and 1,4-diazabicyclo[2.2.2]octane (5.5 g, 49 mmol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-hexane (1:4, v/v) were collected, concentrated and recrystallized from ethyl acetate-hexane to give the titled compound (10.6 g, 88%) as white crystals. The reaction mixture was refluxed for 24 hrs the solvent was evaporated extracted with ethyl acetate The organic layer was washed with saturated brine dried over anhydrous magnesium sulfate The solvent was evaporated The fractions eluted with ethyl acetate-hexane (1:20 v/v) were collected concentrated

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromo-2-hydroxybenzoate (3.0 g) in DMF (50.0 mL) were added tributylvinyltin (6.18 g), bis(triphenylphosphine)palladium(II) chloride (0.46 g) and lithium chloride (4.07 g), and the mixture was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound. This compound was used in the next step without an additional purification. the precipitated insoluble substance was removed by filtration through Celite The filtrate was diluted with ethyl acetate the mixture was washed with water and saturated brine The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of methyl 4-bromo-2-hydroxybenzoate (3.0 g) in DMF (50.0 mL) were added tributylvinyltin (6.18 g), bis(triphenylphosphine)palladium(II) chloride (0.46 g) and lithium chloride (4.07 g), and the mixture was stirred at 90° C. for 2 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound. This compound was used in the next step without an additional purification. the precipitated insoluble substance was removed by filtration through Celite The filtrate was diluted with ethyl acetate the mixture was washed with water and saturated brine The organic layer was dried over anhydrous sodium sulfate the solvent was evaporated under reduced pressure The residue was purified by silica gel column chromatography (ethyl acetate/hexane)